This invention relates generally to apparatus and methods for detecting radiation in order to determine the spatial coordinates of structures within a body, e.g. within the body of, or within a diagnostic tissue sample from, a living being, and for estimating the density of intervening tissue lying between the radiation detecting apparatus and said structures ("intervening tissue"). Specifically, this invention relates to a method and apparatus for utilizing a broad spectrum of photon radiation including x rays, gamma rays, and x rays in conjunction with gamma rays, for diagnostic procedures.
Examples of some specific apparatuses and methods to which this invention relates are: hand-held nuclear uptake probes for use in open surgical procedures, in endoscopic procedures, transcutaneously, in open and closed biopsy procedures, and on ex vivo tissue specimens, as well as nuclear medicine imaging cameras ("gamma cameras"), including those designed for operative use.
The use of radioactive pharmaceuticals known as radiotracers to tag tissue within a patient for affecting the localization and demarcation of this tissue by radiation detecting devices including operative nuclear uptake probes has been disclosed in the medical literature for at least forty years. In the diagnosis and/or treatment of certain diseases, e.g., cancer, substances are introduced into the body that recognize or identify diseased tissue, such as tumors, or other tissues of clinical interest (such as certain lymph nodes). Examples of such substances include Iodine 125, Iodine 131, Phosphorous 32, in appropriate solutions, which are themselves intrinsically radioactive. Other examples are materials such as monoclonal antibodies, peptides, and certain colloids, which have been labelled with radioactive isotopes. The combination of the tissue-recognizing or identifying substance and the radioactive isotope (or "radioisotope") is referred to collectively as a radiotracer; similarly, the radioisotope which can itself recognize tissue of interest (e.g. Iodine 125) is also referred to as a radiotracer.
When injected intravenously, the radiotracer circulates throughout the body. Once the radiotracer encounters the target tissue cells, the radiotracer will adhere to or be absorbed (i.e. "be taken up") by those cells in concentrated amounts. Locations where radiotracers are taken up in concentrated amounts by the targeted tissue cells of clinical interest are known as areas of "specific uptake." Often only a small percentage, e.g., from less than one to five percent, of the total radiotracer injected will actually be taken up at the site of specific uptake. The remainder of the injected radiotracer will circulate to other regions and tissues of the body that are of no clinical interest, e.g., non-cancerous tissue, including circulating blood, and healthy bone marrow, liver and kidneys. The radioisotope of the radiotracer undergoes radioactive decay; that is, over time, the radioisotope experiences spontaneous nuclear transitions resulting in the emission of radiation, which typically includes gamma-ray photons and x-ray photons.
The radiotracer circulates and interacts with tissue and organs located throughout the body, such that these photons are emitted in random directions from locations that are of no clinical interest as well as from locations of specific uptake. Under prior art methods in nuclear medicine, practitioners are interested in detecting and evaluating gamma-ray photons that are emitted from the locations of specific uptake, while seeking to eliminate from the evaluation all photons emitted from sources that are of no clinical interest, e.g. non-cancerous tissue, circulating blood, and disease-free bone marrow, liver, and kidneys.
The energies of the gamma-ray photons emitted by the radioisotopes are unique to each isotope. At the time of their creation, these gamma rays are termed "full energy" or "primary" gamma rays. For the emitted photon to have enough energy to exit the patent's body in sufficient quantities to be able to form an image in a gamma camera, its energy must be above about 60 keV. For radiotracers in common use, the gamma-ray energies may be as high as about 511 keV. As an example, when Technetium 99m, an isotope often used in nuclear medicine, decays, 89% of the time a full-energy 140-keV gamma ray is emitted. Natural abundance ("abundance") or yield refers to the percentage of time that a decay or disintegration of the radioisotope nucleus results in production of the photon of interest, in this case the 140-keV full-energy gamma-ray photon. Indium 111, another commonly used radioisotope, emits 172-keV full-energy gamma rays, with an abundance of 89.6%, and 247-keV full-energy gamma rays, with an abundance of 93.9%.
These gamma-ray emitting radioisotopes also emit characteristic x rays. The characteristic x rays originate in the following way. When the nucleus undergoes radioactive decay, an electron is sometimes removed from one of the orbital shells, most often the inner orbital shell. An electron from one of the outer orbital shells promptly falls back to the inner shell to take the place of the ejected electron so that the atom returns to its ground state. This action results in the emission of a characteristic x ray. The emitted x ray is described as "characteristic" because its energy is characteristic of the specific element involved. Characteristic x-ray emissions from radioisotopes used in nuclear medicine are typically of low energies i.e., from about 15 to 30 keV. For example, the radioactive decay of Technetium 99m results in Technetium characteristic x rays of about 19 keV, with an abundance of 7.5%, in addition to the 140 keV gamma ray previously discussed. The radioactive decay of Indium Ill results in Cadmium characteristic x-rays of approximately 24 keV, with an abundance of 83.5%.
The ratio of the number of full-energy gamma rays to the number of characteristic x rays emitted by each radioisotope is fixed and known, and reflected in the related abundance figures.
Under prior art methods in nuclear medicine, practitioners have typically utilized either the full-energy gamma rays alone in determining the location of cancerous or other tissues of interest in one instance, the combined signal from detection of both x rays and gamma rays together, without separately measuring and comparing the two signals, is being used. This is being done in the NEOPROBE device, made by Neoprobe Corporation of Columbus, Ohio. The NEOPROBE device detects both the 27-keV x rays and 35-keV gamma rays from Iodine 125.
There are several factors that make the evaluation of full-energy gamma-ray photons difficult. These factors have tended to make the detection and evaluation of the characteristic x rays even more difficult. Other than in the NEOPROBE device mentioned above, practitioners have seldom utilized the characteristic x rays and largely have not recognized the utility of the characteristic x ray in nuclear medicine. No practitioners have utilized the separate signals from characteristic x rays and the separate signals from gamma rays, and compared them to each other, in order to determine the spatial coordinates of tissue with nuclear uptake, or of the density of intervening tissue. Some of the problems associated with the use of both full-energy gamma rays and characteristic x rays, together and separately, to locate tissues of interest are discussed below.
Soft tissue in the human body is largely water, with small admixtures of light elements. Therefore soft tissue, blood, and most tumors have similar densities, approximately that of water. Bone is much denser, while lungs, because of their large air content, have effective densities much less than water. The probability of photons being absorbed as they move through matter is exponential. Gamma rays with energies from 60 to 500 keV usually travel relatively long distances before absorption in soft tissue (several hundred millimeters), whereas characteristic x rays of about 20 to 30 keV usually travel substantially shorter distances (30 millimeters or less). Consequently, these x rays cannot create images in gamma cameras because they are virtually all absorbed by fat, muscle, and skin.
Furthermore, as previously mentioned, in addition to being taken up in tissue of clinical importance, imaging radiotracers may also be taken up in tissues and body fluids, such as blood, that are not of clinical interest. In the instance of Indium-111 labeled cancer-seeking antibodies, for example, a twenty-gram tumor may have only one percent of the total injected radiopharmaceutical dose, whereas the liver may have thirty five percent of the injected dose, on a non-specific basis (i.e., with no cancer present in the liver). The number of detected full-energy gamma rays from said liver, as measured by a hand-held nuclear uptake probe, may be from ten to one hundred times greater than those from the tumor. Significant radiation activity may also persist in circulating blood and in disease-free bone marrow throughout the body. As another example, Technetium 99m-labeled antibodies often show strong nonspecific uptake in the kidneys. This non-specific uptake in tissues which are not of clinical interest is an important source of background radiation.
The photons that lose energy and change direction due to the process known as Compton scattering represent additional background radiation. Compton scattering takes place when a photon interacts with an electron, and thereby loses energy and changes direction. The Compton scattering which results from the interaction of incident gamma photons with electrons of body tissues creates a virtual sea of scattered photons having energies ranging from slightly below the full-energy gamma-ray photons down to and below typical x ray energies ("the Compton continuum"). The directions, and thus the apparent points of origin of these Compton-scattered photons have only a limited relationship to the site from which the original, unscattered, full-energy gamma rays originated, and therefore have little relationship to the location of the tissue of interest.
The widespread distribution of radiotracers often encountered in tissues which are not of clinical interest described above, including the relatively high preferential uptake in certain organs, plus the additional radiation from Compton-scattered photons contributes to nonuniform and sometimes very intense levels of non-specific background radiation.
Under prior art methods, these marked variations in background radiation, including misleading signal from organs with no disease but high uptake, plus the abundant, almost randomly- directed Compton-scattered photons have seriously compromised the search for specifically labelled tissue with hand-held probes and with gamma cameras. Further, the Compton-scattered photons add background radiation and compete for processing time with signal corresponding to unscattered gamma rays and x rays.
There are additional drawbacks associated with prior art methods of detecting full-energy gamma ray photons. The attenuation by body tissues of full-energy gamma-rays from very small tumors located deep within the patient's body have resulted in an inability of gamma cameras to locate many such sites. This problem is made more severe because some tumors simply fail to take up enough radiotracer to be detected at a distance. Since 1949 operative nuclear uptake probes have been used by surgeons in an effort to overcome these drawbacks.
Prior art hand-held nuclear uptake probes can be classified into two categories, contact probes and extended-range probes. Contact probes have been used to detect radiation having a short range, such as electrons and positrons from beta decay, and relatively low energy photons (i.e., below 60 keV). Examples are the 27-keV x rays and 35-keV full-energy gamma rays of Iodine 125. These contact applications are characterized by significant reduction in the number of full-energy photons detected due to the absorption and/or scattering of the radiation that occurs in overlying or commingled tissue of only a few millimeters depth. Consequently, contact probes are limited to applications wherein the probe is essentially in contact with the radiolabeled tissue of interest. This limitation is an advantage in situations of modest specific tissue uptake coupled with high non-specific background radiation from underlying tissue, such as is the case with some radiolabeled monoclonal antibodies. Such contact probes share features of excellent localization when radiolabels are used that emit only lower energy photons with short ranges in tissue, as is the case with Iodine 125. However, gamma camera images cannot be obtained of tissues labeled with radiotracers that emit only short-ranged radiation, as mentioned earlier. Further, it is difficult to use such contact nuclear uptake probes to scan tissues for radiolabeled sites of unknown depth.
As reported in an article entitled "The Clinical Use Of Radioactive Phosphorous", in the Annals of Surgery, Vol. 130, pps. 643-651 (1949), by Selverstone, Sweet, and Robinson, those authors used a contact hand-held nuclear uptake probe to determine boundaries of resection in a glioblastoma multiforme. They used Phosphorus-32 which emits a beta particle. These were detected with a blunt needle Geiger-Mueller detector. In this instance signal-to-noise ratio was excellent because the normal brain has an intact blood brain barrier which excludes Phosphorus. The short range of about one millimeter of the Beta particle in tissue obviated background from bone marrow as well as from more distant sources. No use of characteristic x rays and gamma rays was made by Selverstone, et al.
The use of extended-range nuclear uptake probes was reported by Craig, Harris, et al, in an article entitled "A CSI--Crystal Surgical Scintillation Probe", in Nucleonics, Volume 14, pps. 102-108 (November 1956). In a case of post-operative residual tissue, tissues labelled with Iodine 131, which emits full-energy 364-keV gamma rays, were localized using a Cesium Iodide scintillation-crystal-based hand-held nuclear uptake probe. This probe used a light pipe to transmit the scintillation signal to a photomultiplier tube. The very high physiological concentration of Iodine 131 by the thyroid provided large numbers of detected photons while absence of other Iodine concentrations in the neck minimized background radiation. Shielding and collimation were used to minimize detection of background radiation from Iodine 131 in the gastric mucosa. In 1971, A. C. Morris, T. R. Barclay, A. Tanida, et al. reported on using a transistorized version of this CsI probe in an article entitled "A Miniaturized Probe For Detecting Radioactivity At Thyroid Surgery", in Physics In Medicine And Biology, Volume 15, pps. 397-404 (1971).
Under conditions of high uptake in the tissue of interest, rapid blood pool clearance, and low non-specific uptake, probe localization of radiolabelled tissues can be relatively easy. Current Technetium 99m sulfur colloid lymph node mapping techniques for finding the sentinel node in melanoma and breast cancer approach this ideal. Imaging provides a map of the actual anatomic distribution of lymph node drainage patterns, while the probe readily finds small nodes deep in fat and other tissue.
Many radiotracers are far from ideal for probe use because of limited tumor-to-background contrast, abundant far-field non-specific uptake, and slow blood pool clearance relative to the physical half life of the radioisotope. Indium 111 labelled monoclonal antibodies, such as Oncoscint.RTM. marketed by Cytogen Corporation, has about 0.05% injected dose per gram of tumor. The signal from this low dose competes with that from about 35% of the dose in the 1800 gram liver. As mentioned previously, this can result in full-energy gamma rays from said liver, as measured by a hand-held nuclear uptake probe, being from ten to one hundred times greater than those from the tumor.
There is also significant uptake in the bone marrow, and in circulating blood. On Nuclear Medicine scans, tumor is about the same density as imaged large blood vessels, which are commonly immediately adjacent to tumor involved lymph nodes.
Neoprobe Corporation provides a device for a method wherein a tumor-seeking monoclonal antibody is tagged with the radioactive isotope Iodine-125 and injected into the body to determine the location of cancerous tissue. See U.S. Pat. Nos. 4,782,840, 4,801,803, and 4,893,013. Iodine 125, whose half-life is 60 days emits a full-energy 35-keV gamma-ray at the low energy of 35 keV and a 27-keV characteristic x-ray. These photons are detected in a single broad energy window by the practitioner during surgical exploration with the use of a hand-held contact nuclear uptake probe. The relatively long half-life of 60 days (i.e., long compared to that of many other imaging nuclear medicine radioisotopes) allows the practitioner to wait until much of the radiotracer has been biologically cleared from the blood pool and the background radiation has been much reduced. However, this process reportedly takes about three weeks, and thus causes a corresponding delay of surgery. This delay is considered by some practitioners to be a disadvantage. In addition, the low energy photons can not be used for preoperative imaging by gamma cameras. If a Technetium-99m bone scan or Indium-111 white cell scan is done close to the scheduled date of surgery, background radiation arising from Compton scattering of full-energy gamma rays emitted by Technetium or Indium can make Iodine-125 localization extremely difficult. The NEOPROBE device uses a single energy "window" or band wide enough to include both the 27-keV characteristic x ray and the full-energy 35 keV gamma ray, and thus cannot distinguish between these two photons.
Other techniques employed with hand-held surgical nuclear uptake probes to deal with background radiation have included: control measurements of uptake of adjacent tissues, using identical probe angular orientation; aiming the probe consistently away from all organs with high non-specific uptake, with extended-field probes; use of a hand-held or hand-placed radiation blocking plate, with extended-field probes; use of a "window" which limits the photons measured by the radiation-detecting system to those of energies close to that of the full-energy gamma-ray peak; and the use of collimation appropriate to the size and also the depth of the lesion.
Operative nuclear uptake probes augmented by radiation blocking plates and selectable collimation are the subjects of U.S. Pat. Nos. 5,148,040, 4,959,547, and 5,036,210.
While each of these techniques has markedly reduced the problems caused by non-specific background radiation, there are circumstances in which one or more of these techniques can not be easily employed, the methods are sometimes time-consuming, or a high degree of familiarity and specific experience is required of the practitioner.
For example, extended-field probes are challenged by applications involving Indium-111 labelled antibodies. About 35 percent of the activity can be from non-specific liver uptake. Tumor activity is often diffusely present throughout the bone marrow, and the tumor activity per gram is often similar to that found in circulating blood. Despite techniques such as aiming the probe to avoid sites of known high non-specific uptake, use of selectable collimation, and use of a radiation-blocking plate where anatomically possible, the acquisition of good intraoperative skills by the practitioner can be very time-consuming.
Contact probes, on the other hand, are severely limited by attenuation by overlying tissue of only a few centimeters thickness. The tissue of interest, such as a tumor, must be almost completely exposed and essentially in contact with the probe in order for the probe to detect the uptake. Consequently, it is difficult to use contact nuclear uptake probes to scan tissues for radiolabelled sites of unknown depth, or, for example, to explore for retroperitoneal nodes during colorectal procedures without surgically penetrating the peritoneum. Gamma camera images cannot be obtained using many of the radioisotopes used with contact probes, such as Iodine-125.
Compton-scatter correction for gamma camera imaging has been discussed in various articles. See for example, K. W. Logan and W. D. McFarland, "Single Photon Scatter Compensation By Photopeak Energy Distribution Analysis", IEEE Transactions on Medical Imaging, Vol. 11, pps. 161-164, June 1992 U.S. Pat. No. 4,873,632 (Logan et al.) discloses a system utilizing filtering to reduce background radiation introduced by Compton-scatter in imaging by means of a gamma camera.
U.S. Pat. No. 3,843,881 (Barton) discloses a method for detecting the presence of metals in subterranean formations. Under Barton, a formation is irradiated with high energy electromagnetic radiation from a suitable source, such as radioactive material. Characteristic x rays are emitted from the metals as the result of being irradiated. These x rays are detected and measured to provide information regarding the presence and type of metal ore in the formation. Barton does not disclose the measuring and comparing of the gamma ray to a characteristic x ray to determine lateral location and depth of radiolabelled objects, or depth of intervening material. Further, Barton does not make use of the display of gamma-ray or x-ray photons stripped of the display of radiation from Compton-scattered photons.
U.S. Pat. No. 4,949,365 (Koike) describes an apparatus for measuring the density of objects such as bones, by transmitting gamma rays having different energy levels. Koike does not make use of characteristic x rays and/or full-energy gamma rays for the measuring spatial coordinates. Further, Koike does not make use of the display of gamma-ray or x-ray peaks stripped of the display of radiation from compton-scattered photons.
U.S. Pat. No. 3,936,646 (Jonker) describes a focusing collimator kit with multiple stackable components for isotope imaging. This patent does not disclose the use of combined characteristic x rays and gamma rays in the determination of spatial coordinates of the tissue detected, or of the density of intervening tissue. Further, Jonker does not make use of the display of gamma-ray or x-ray peaks stripped of the display of radiation from Compton-scattered photons.
U.S. Pat. No. 4,150,289 (Rosauer) describes a gamma-ray inspection system for measuring the wall thickness of a tubular product, and in particular an associated calibration block. This patent does not disclose the combined use of characteristic x rays and gamma rays in the determination of spatial coordinates of the material detected, or of the density of intervening material. Further, Rosauer does not make use of the display of gamma-ray or x-ray peaks stripped of the display of radiation from Compton-scattered photons.
U.S. Pat. No. 4,340,818 (Barnes) describes a scanning grid apparatus used in x-ray radiology that provides improved transmissivity of full-energy x rays passing through the subject while providing reduced scatter radiation penetration. This patent does not disclose the combined use of both characteristic x rays and full-energy gamma rays in the determination of spatial coordinates of the tissue detected, or of the density of intervening material. Further, Barnes does not make use of the display of radiation from Compton-scattered photons.
U.S. Pat. No. 4,419,585 (Strauss) describes a variable angle radiation collimator used in a gamma camera system for radiological examination of human subjects. The collimator proves collimation of gamma rays so as to transmit radiation in a predetermined orientation. This patent does not disclose the combined use of both characteristic x rays and full-energy gamma rays in the determination of spatial coordinates of the tissue detected, or of the density of intervening tissue. Further, Strauss does not make use of the display of gamma-ray or x-ray peaks stripped of the display of radiation from Compton-scattered photons.
U.S. Pat. No. 4,489,426 (Grass) describes a collimator for regulating the shape and size of the pattern of radiation projected on a radiation detector from a radiation source, particularly for regulating the beam of radiation in a medical diagnostic x-ray machine. This patent does not disclose the combined use of both characteristic x rays and full-energy gamma rays in the determination of spatial coordinates of the tissue detected, or of the density of intervening tissue. Further, Grass does not make use of the display of gamma-ray or x-ray peaks stripped of the display of radiation from Compton-scattered photons.
U.S. Pat. No. 5,068,883 (DeHaan) describes a contraband detection system employing two different sources of low-energy gamma rays, and a means of detecting backscatter from inspected objects. Depending upon the composition of the target volume, a portion of the gamma rays are backscattered and returned to the hand-held device. By quantitatively sensing these backscattered gamma rays, a rough qualitative determination can be made as to the density composition of the target volume. From such density information, reasonable inferences may be drawn as to whether the target volume includes certain types of contraband material. This patent does not disclose the combined use of both characteristic x rays and gamma rays in the determination of spatial coordinates of the material detected. Further, DeHaan does not make use of the display of gamma-ray or x-ray peaks stripped of the display of radiation from Compton-scattered photons.
Therefore, for the foregoing reasons, the prior art methods and devices used in nuclear medicine suffer from one or several drawbacks. Further, many of the prior art methods and devices relating to the use of radioactive isotopes do not disclose the use of both characteristic x rays and gamma rays, separately and/or simultaneously, in the determination of spatial coordinates of the tissue detected, or of the density of intervening tissue. Nor do they make use of the display of gamma-ray or x-ray peaks stripped of the display of radiation from Compton-scattered photons.